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MDR & XDR TUBERCULOSIS

MODERATOR : DR PANKAJ ABROL PRESENTED BY: DR VIRENDER VERMA

MDR & XDR TUBERCULOSIS


Definition Epidemiology Etiology Diagnosis Treatment Special situation

Introduction
Mycobacterium tuberculosis has been present in the human population since antiquity

1882 - Robert Koch discovered Mycobacterium tuberculosis

Introduction (Contd..)
Sanatorium - The first step against TB. Measures available to doctors were still modest
Improve social and sanitary conditions Reduction of the lung volume( Thoracoplasty ) Radiation

1943 - Streptomycin 1963 - Rifampicin

Introduction (Contd..)
Resistance to Streptomycin emerged in 85% cases
BMJ 1948;2:10091015

Mid-1990 - Most countries registered MDR-TB


N Engl J Med 1993;328:521-6

2006 XDR TB term was coined


Morb Mortal Wkly Rep 2006; 55: 30105

Definition
Mono Resistance: Resistant to one drug Poly-Resistance: Resistant to more than 1 drug MDR-TB: Resistant to at least isoniazid and rifampicin with or without resistance to other drugs XDR-TB: MDR-TB + any one of the fluoroquinolones + one of three injectable second-line drugs (Amikacin, Capreomycin or Kanamycin)

MMWR 2006;55:1176 WHO

Epidemiology
An estimated 9.2 million new cases of TB in 2006 (139 per 100 000 population)
4.1 million new smear-positive cases (44% of the total) 0.7 million HIV-positive cases (8% of the total)

An estimated 14.4 million prevalent cases Estimated 1.5 million deaths from TB in HIV-negative people Estimated 0.2 million death among people infected with HIV.

Semin Respir Crit Care Med 2008;29:481491

Estimated number of new TB cases


Asia accounts for 55% of

Epidemiology

global cases, and Africa accounts for 31% India ranks 1st Incidence-168/1lkh pop/yr Prevalance-299/1lkh pop/yr

Highest no of cases

WHO REPORT 2008 | GLOBAL TUBERCULOSIS CONTROL

Epidemiology(Contd)
An estimated 489,139 cases of MDR-TB in 2006 Accounts for 4.8% of all TB cases Increase of 12% since 2004 and 56% since 2000 China and India carry approximately 50% of the global burden of MDR-TB

Semin Respir Crit Care Med 2008;29:481491

MDR PREVALENCE HIGHER THAN 5.0% AMONG NEW CASES 2002-2007


22.3%

WHO/IUATLD Drug Resistance Surveillance. 2008

MDR PREVALANCE HIGHER THAN 30% AMONG PREVIOUSLY TREATED CASES, 2002-2007
60.0%

WHO/IUATLD Drug Resistance Surveillance. 2008

MDR prevalence in south east Asian region

WHO/IUATLD Drug Resistance Surveillance. 2008

Epidemiology(Contd..)
The overall prevalence of XDR-TB is 2% 7% of total MDR TB cases are XDR-TB Countries conducting routine surveillance- XDR represent between 7% &34% of MDR isolates

The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 2002-2007 The Global MDR-TB & XDR-TB Response Plan 20072008

Till June 2008, 49 country have reported confirmed XDR-TB cases to WHO

Prevalence of drug resistance in new cases

Adapted from, Sharma et al TUBERCULOSIS

Prevalence of drug resistance in previously treated patient

Adapted from, Sharma et al TUBERCULOSIS

Drug resistant data from survelance sites

Adapted from, Sharma et al. TUBERCULOSIS

Epidemiology(Contd)
In India an estimated 110 132 cases of MDR-TB in 2006 Accounts for 4.8% of all TB cases Prevalence among new cases - 2.8% Prevalence among treated cases -17.2%. For XDR - 7.4% & 9.3% among MDR-TB

WHO REPORT 2008 | GLOBAL TUBERCULOSIS CONTROL

Aiims Data
Primary MDR- 6% Acquired MDR- 24% XDR- 4%

Aiims microbiology department

Molecular basis
Drug resistance can be achieved by.
Barrier methods Degrading or inactivating enzyme Drug target modifications
Natural resistance

Resistance to ATT

MDR-TB reflects step wise accumulation of individual mutation Spontaneous mutations leading to resistance occur at random

Tubercle 1987; 68:518 Lancet 1994; 344:2938

Mechanism of drug action

National Institute of Allergy And Infectious Disease

Mechanisms of drug resistance

Thorax 1998;53:793797

WEIGHTED MEAN OF RESISTANCE TO SPECIFIC DRUGS

In new cases

In previously treated cases

The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 2002-2007

Amplifier effect of short course chemotherapy

Semin Respir Crit Care Med 2008;29:499524

Host factor
The frequencies of DRB101and of DQB10502 significantly decreased in the MDR-TB DRB114 occurred in 30.9% of MDR cases 6.8% in the drug sensitive cases Patients with HLA-DRB114 have a eight-fold risk of developing MDR-TB Odd ratio = 8.2

Sharma S K et al. Infection, Genetics and Evolution 3 (2003) 183-188

Agent factor
The most wide spread Mycobacterium tuberculosis strains are of Beijing family W-Beijing genotype strong association with multidrug resistance Method - Restriction fragment length polymorphism (RFLP) analysis of IS6110 insertion World wide prevalent

Int J Tuberc Lung Dis 2005; 9:646653

Factors related to previous treatment


MDR-TB is a man-made phenomenon poor treatment, poor drugs and poor adherence lead to the development of MDR-TB. Most powerful predictor of presence of MDR-TB is a history of previous treatment In management most common error is adding single drug to failing regimen

Indian J Med Res 2004; 120:354376

Causes of inadequate treatment

Lambregts et al. Tubercle and Lung Disease 1995: 76; 455-458

Diagnosis
MDR-TB and XDR-TB are pure laboratory diagnosis
Quality assured accredited laboratories mandatory for accurate diagnosis of drug resistant TB Component of quality assurance programme Quality control Quality improvement Proficiency testing

Supranational reference Laboratory Network

TRC
WHO/IUATLD Drug Resistance Surveillance. 2008

Who should go for drug sensitivity test?


MDR Suspect

A TB patient who fails an RNTCP Category I or III treatment regimen Any RNTCP Category II patient who is sputum smear positive at the end of the fourth month of treatment or later. Concurrent illness such as epilepsy, alcoholism, renal and hepatic problems, psychiatric illness Excluded Under 15 years of age; Having had >1 mth t/t with second-line anti-TB drug.

RNTCP DOTS-Plus Guidelines,2008

Laboratory aspect
Sputum should be good and satisfactory Specimen should be transported as soon as possible
If delay Refrigeration Preservation -1% Cetyl Pyridinium Chloride (CPC) + 2% NaCl

Sputum container labelled as BIO- HAZARD Homogenisation and decontamination Inoculation and incubation

RNTCP DOTS-Plus Guidelines,2008

Methods of Drug susceptibility


Conventional method Culture uses Lowenstein-Jensen (LJ) or 7H11 solid media Takes long time - 6-8 week Sensitivity limited by availability of bacilli in sample Methods
Absolute Concentration Method The Resistance Ratio Method Proportion Method

Proportion method
Method of choice: Recommended by DOTS-Plus 10-fold dilutions of inoculum are planted on both control and drug containing media Resistant portion as a percentage of the total population tested CRITERIA OF RESISTANCE Any strain with 1% (the critical proportion) of bacilli resistant to any of the four drugs

Automated liquid based culture


BACTEC 460-TB
Based on microbacterial metabolism Faster than solid culture

MB/Bact T system
Based on detection of CO2 DST 8 to 12 days

BACTEC Mycobacteria Growth indicator Tube (MGIT)960


Consumption of oxygen DST 8 to 12 days

Versa Trek system


Based on detection of gases
J Clin Microbiol 1998; 36:2940-2943

Phage-based tests
Luciferase reporter phages
Infected bacteria emit light Results in 2 days post culture Limited reports of clinical application

FAST Plaque TB-RMP test


Plaques of lysed cells counted Results in 2-3 days Cannot be used for children or HIV-positive patients

S Afr Med J. 2007;97:858-863 J Infect. 2005;51:175-187.

Others
Microscopic-Observation Drug-Susceptibility assay (MODS)
DST for first line drugs Report within 7 days Simple, rapid & low cost

Nitrate reductase assay


Sensitivity and specificity 90%.

Colorimetric method
For isoniazid and rifampicin

N Engl J Med. 2006;355:1539-1550 Antimicrob Agents Chemother. 2003;47:3616-3619.

Molecular method
DNA sequencing
Most accurate and reliable method for mutation detection Detect both previously recognized and unrecognized mutations For rifampicin only

The Line Probe assay (LiPA)


Detect rpoB mutations of rifampicin Result in less than 48 hours

J Clin Microbiol. 2007;45:2635-2640

GenoType MTBDR test


Test available within one day Sensitivity- 98.8% specicity - 100%

J Clin Microbiol 2005; 43: 3699-3703.

Diagnosis(Contd..)
DNA microarrays
Based on the principle of hybridization Detect Rifampicin resistance only Analysis large amounts of DNA sequences

Molecular beacons
Sensitive enough to detect 2 bacilli, Results in 3 hours

Single-strand conformation polymorphism (SSCP) Fluorescence resonance energy transfer (FRET) probes

Genome Res 1998;8:435-48. Methods Mol Biol 2003;212:111-28

Difficulty in testing susceptibility of 2nd line drugs


In vitro drug instability Drug loss due to protein binding Heat inactivation Incomplete dissolution Filter sterilization Varying drug potency Critical concentration very close to the minimal inhibitory concentration (MIC)

Guidelines for mangt of DR-TB Update 2008 WHO

Prevention
Self administered therapy is inferior to DOTS

Fixed dose combination (FDC) can be a cost effective strategy, only somewhat inferior to DOTS
DOTS the most cost effective intervention in the control of TB DOTS the most cost effective prevention for MDR & XDR- TB

Int. J. Tuberc. Lung Dis. 2000; 4: 2017

DOTS in MDR TB: cure rate: 60% recurrence rate: 28%

JAMA 2000; 283: 253745. Int. J. Tuberc. Lung Dis. 2002; 6: 85864. WHO/HTM/TB/2006.361

Programme strategies
Standardized treatment
On the basis of DRS data All patients receive the same regimen

Empirical treatment
Individually designed Based on history of antituberculosis treatment &DRS data

Individualized treatment
Based on history of antituberculosis treatment & DST

Basic principles
Patient suspected of drug resistance, must under go culture & DST Patient should immediately started with treatment A single drug should never be added to failing regimen Drugs with potential cross resistance should never be used At least 3 previously unused drugs to which there is in vitro susceptibility , must be employed Based on the history of drugs taken Minimum duration is 18 months post culture conversion

Classes of antitubercular drugs

guidelines for the programmatic mngmt of DR tuberculosis. who 2008

Use any available Group 1: First-line oral agents Plus one of these Group 2: Injectable agents Plus one of these Group3: Fluoroquinolones Pick one or more of Group 4: Second-line oral bacteriostatic agents

Consider use of these Group 5: Drugs of unclear role in DR-TB treatment

MDR TB suspect referred from MO-PHI to DTO with Copy of the Cat II (and Cat I/III) Rx card
Request for culture and DST form Drug-o-gram

DTO confirms suspect and sends sputum samples to IRL with


Request for culture and DST form Drug-o-gram

Enter in Culture and DST register at DTC


continues Cat II treatment Culture and DST results communicated to the DTO electronically Non MDR TB Continue Cat II MDR TB

Patient traced by DTO with the help of MO-TC and STS. Patient counselled and referred to DOTS Plus site RNTCP DOTS-Plus Guidelines,2008

RNTCP CATEGORY IV REGIMEN


6 (9) Km Ofx Eto Cs Z E / 18 Ofx Eto Cs E

RNTCP DOTS-Plus Guidelines,2008

Surgery
Indications
Localized disease High probability of failure or relapse with medical therapy

3 months chemotherapy prior to surgery Bilateral disease does not preclude surgical intervention, unless extensive Excellent cure rates 90% with post-surgery chemotherapy

Clin. Chest Med. 1997; 18: 12330 Ann. Thorac. Surg. 2005; 79:95963

Surgery(Contd..)
Poor prognosis
Low BMI (<18.5 kg/m2) Bacillary resistance to ofloxacin Cavitation beyond the range of surgical resection

Complications: Respiratory failure, Bronchopleural fistula, Infections, Empyema, wound Adjunctive surgical procedures : Myoplasty, Omentoplasty, Thoracoplasty

Eur Respir. J. 2006; 28: 57680

Immunotherapy
Mycobacterium vaccae Mycobacterium w Cytokine therapy interferon-g Interferon- Interleukin-2 (IL-2) Others Thalidomide Pentoxifylline Imiquimod Levamisole

Transfer factor Inhibitors of transforming growth factorInterleukin-12


Clin. Exp. Immunol. 2005; 141:5418. Respir. Med. 2001; 95: 4447.

Exploratory approach
Local instillation of antimycobacterial agent Plant products: cerulenin, transcinnamic acid, Flourensia etc Imipenem in murine model New delivery system: liposomes, solid lipid nano particles

Int. J. Antimicrob. Agents 2007; 29: 33840

Newer therapy

The American Journal of Medicine (2008) 121, 835-844

Infection control measures


Administrative controls
Reduced hospitalisation Rapid drug-susceptibility assays Detention for confirmed XDR tuberculosis patients

Environmental controls
Airborne Infection Isolation (AII) room High-Efficiency Particulate Air (HEPA) Filter Ultraviolet germicidal irradiation (UVGI)

Personal respiratory protection


Respirator Surgical masks for patient
MMWR December 30, 2005 / 54 (RR17); 1-141

Treatment outcomes
Short course chemotherapy is ineffective for controlling established MDR-TB
Cure rate 60% Recurrence rate 28%

Cure rates up to 75% can be achieved with individualized regimen XDR-TB co infected with HIV, mortality is very high Kwazulu Natal study 52 out of 53 XDR cases died

Sharma S K et al.Indian J Chest Dis Allied Sci. 1996 38(2):73-9 N Engl J Med 1993; 328: 52732

Outcome(contd..)
Total 801 patients referred among this 651 tested 651 patients tested
XDR-TB - 48 (7.4%) MDR-TB- 603 (92.6%)

Use of Comprehensive treatment with5 drugs (incl fluoroquinolone and injectables) at highest tolerated dose, T/t >2 years, drug susceptibility done to design and adjust regimens. Cured or completed the treatment
XDR-TB- 29 (60.4%) MDR-TB 400 (66.3%)
N Engl J Med 2008;359:563-74

Outcomes(contd..)

N Engl J Med 2008;359:563-74

Cure rates
Study, year of publication Goble et al, 1993 Sharma et al, 1996 Park et al , 1998 Yew et al, 2000 Type of DR-TB MDR-TB [ n = 171] MDR-TB [ n = 19] MDR-TB [ n = 107] MDR-TB [ n = 63] Treatment Outcome 65% cured, treatment failure 35% Sputum conversion in 18 cases out of 19 82.5% cured, treatment failure 17.5% 81% cured, treatment failure 14.3%, death 4.7% Cured or completed treatment 77%, default 11%, treatment failure 8%, death 4% 83% cured, death 8% Cured or completed treatment 69.7%, treatment failure 6.7% 52 of the 53 patients died 41.6% cured, treatment failure 38.7% 60.4% with XDR-TB completed treatment or cured; 66.3% with MDR-TB completed treatment or cured Adapted from, Sharma et al TUBERCULOSIS

Tahaoglu et al, 2001

MDR-TB [ n = 158]

Mitnick et al, 2003 Nathanson et al, 2006 Gandhi et al, 2006 Sharma, 2007 Mitnick et al, 2008

MDR-TB [ n = 75] MDR-TB [ n = 1047] XDR-TB [ n = 53] MDR-TB [ n = 172] XDR-TB [ n = 1] XDR-TB [ n =48] MDR-TB [ n = 603]

Poor prognosis
HIV Extrapulmonary involvement Low haematocrit Low BMI Older age Alcoholism Bacillary and treatment characteristics Extensive drug resistance Resistance to ofloxacin in vitro previous treatment failure to apply appropriate therapy Poor adherence during treatment

Management of contacts
Identify through contact tracing If contacts have active disease the culture & DST required Clinical follow up for a period of at least 2 year If active disease then prompt MDR-TB regimen WHO not recommended 2nd line drugs as Suggested regimens
Pyrazinamide plus Ethambutol Pyrazinamide plus Quinolone

Am J Respir Crit Care Med 2000; 161(4 Pt 2) : 221-47 Guidelines for mangt of DR-TB Update 2008 WHO

MDR & XDR-TB and HIV


African region has high burden for both HIV and TB TB -Most common opportunistic infection in HIV Risk of reactivation : 5 to 8 per cent per annum Cumulative lifetime risk : 30 % No predisposes for MDR-TB High risk of mortality, especially when diagnosed late

AIDS 1998; 12 : 191-5 Thorax 2002; 57: 81016

Contd...
Antiretroviral therapy must Efavirenz is the preferred drug to be used in patients on ATT Drug interaction uncommon with 2nd line drugs
ex FluoroquinoloneDidanosine

Higher rate of adverse drug reaction Extrapulmonary localization, independent poor prognostic factor .

Am. J. Respir. Crit. Care Med. 2001; 164

Children
Transmission of MDR-TB from adult patients to children could occur Adverse drug reactions are common. Reasonably good cure rate Fluoroquinolones- Conflicting evidence Weight loss / absence of satisfactory weight gain is suggestive of treatment failure

WHO/HTM/TB/2006.361 Hampel B et al. Pediatr. Infect. Dis. J. 1997; 16: 1279

Pregnancy
Not a contraindication for treatment of MDR-TB Therapy may be delayed until the second trimester Avoid aminoglycoside Ethionamide can aggravate nausea and vomiting in pregnant women Infant formula is good alternatively to breast feeding Outcome is good

Chest 2003; 123: 9536.

Summary
MDR & XDR tuberculosis pose greater challenge for effective TB management Poor treatment, poor drugs and poor adherence lead to the development of drug resistance MDR-TB and XDR-TB are pure laboratory diagnosis Need for new methods for early diagnosis

Summary(Contd..)
DOTS treatment for TB patients is the most cost effective method of preventing MDR TB Prompt diagnosis early treatment is prerequisite for all programmes Adjuvant therapy should be use whenever possible Comprehensive and individualized treatment have good prognosis compared to standardized treatment

Thank you

21-female H/O Cough, Shortness of breath for 2 years Associated with blackish sputum only during menstruation Weight loss and reduction in appetite ATT 1 year for this illness Examination: No LAP Chest: Bilateral crepitations CVS and Abdomen: Normal

DIFFERENTIALS:
Interstitial lung disease Lymphangiomyomatosis Catamenial Lung Atypical infections

Fibre-optic bronchoscopy:
Bronchial washing : AFB positive
Culture: Mycobacteria tuberculosis Resistance: HRE Sensitive: Fluoroquinolone, cycloserine, Streptomycin